Obesity is a significant health problem due to its serious medical complications that include co-morbidities such as hypertension, insulin resistance, diabetes, coronary artery disease and heart failure (collectively referred to as Metabolic Syndrome). Obesity and its related co-morbidities continue to cause rising health issues in the developed world and are beginning to affect the developing world as well. The negative health consequences of obesity make it the second leading cause of preventable death in the United States and impart a significant economic and psychosocial effect on society. See, McGinnis M, Foege W H., “Actual Causes of Death in the United States,” JAMA, 270, 2207-12 (1993). Clearly, there is a need to identify and develop new medications that treat and/or prevent obesity and its associated co-morbidities.
Although the clinical data using naltrexone have been inconsistent, there is considerable support in the literature implicating opioid receptors in the regulation of energy homeostasis, thus suggesting that antagonism of one or more of the opiate receptor subtypes can be a suitable target for the treatment of obesity. See, e.g., Hadcock, J. R., et al., “Role of opiates and their receptors in the regulation of food intake and body weight,” Drug Discovery Today: Therapeutic Strategies, 2(2), 171-175 (2005). Although naltrexone is useful for the treatment of alcohol abuse and dependence, poor weight loss efficacy was observed in rodents and humans. It is speculated that this poor weight loss may be due to partial agonism at the kappa and delta opioid receptors.
Pan-selective opioid receptor antagonists (e.g., LY255582) have been shown to provide robust anorectic effects. See, e.g., Gackenheimer, S. L., et al., “Localization of opioid receptor antagonist [3H]-LY255582 binding sites in mouse brain: Comparison with the distribution of mu, delta and kappa binding sites,” Neuropeptide, 39, 559-567 (2005): Shaw, W. N, et al., “The effect of the opioid antagonist LY255582 on body weight of the obese Zucker rat,” Int J Obes, 15(6), 387-95 (1991): Shaw, W. N., “Long-term treatment of obese Zucker rats with LY255582 and other appetite suppressants,” Pharmacol Biochem Behav, 46(3), 653-9 (1993): and Levine, A. S., et al., “Central administration of the opioid antagonist, LY255582, decreases short- and long-term food intake in rats,” Brain Res, 566(1-2), 193-7 (1991). Compounds that act as inverse agonists or antagonists at the mu, kappa and delta opioid receptors have also been reported. In particular, LY515300 (1-(3-cyclohexyl-3-hydroxypropyl)-3(R),4(R)-dimethyl-4-(3-hydroxyphenyl)piperidine) has been shown to have subnanomolar binding affinity for the mu and kappa opioid receptor subtypes, but has a lower affinity for the delta opioid receptor. See, e.g., Statnick, M. A., et al., “Na+-dependent high affinity binding of [3H]LY515300, a 3,4-dimethyl-4-(3-hydroxyphenyl)piperidine opioid receptor inverse agonist,” Eur J Pharm, 482, 139-150 (2003): and Zimmerman, D. M., et al., “Structure-activity relations of trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine antagonists for mu- and kappa-opioid receptor,” J Med Chem 36(20), 2833-2841 (1993).
Although many opioid receptor antagonists are known, there remains a need to identify compounds having improved efficacy and therapeutic indices, in particular for the treatment of obesity and obesity-related co-morbidities.